Neurology

Neurological conditions can act on the entire body and often require treatment plans that include several different medications. There are currently over 170 FDA approved drugs that are commonly prescribed to neurology patients. Epilepsy and Parkinson's disease medications have been implicated in Adverse Drug Reactions as well as drug-induced hypersensitivity syndrome (3). The incorporation of pharmacogenetics in neurology can greatly increase medication efficacy while decreasing toxicity and adverse reactions.

Neurology Relevant Genes In The PRIMER Panel

Gene - Gene Product Description

CYP2D6 – Metabolizes more than 25% of all drugs, including tamoxifen, many antidepressants, antipsychotics, beta-blockers, and opioids.  Detecting variants of the CYP2D6 gene that cause altered enzymatic activity can identify patients who may be at increased risk of having adverse drug reactions or therapeutic failure to standard dosages of CYP2D6 substrates.  Medications which require activation or inactivation by CYP2D6 should be used with caution in patients with CYP2D6 variants.

CYP2C19 – Metabolizes approximately 10-15% of all drugs, including clopidogrel, citalopram, diazepam, and many of the proton pump inhibitors.  Detecting variants of the CYP2C19 gene that cause altered enzymatic activity can identify patients who may be at increased risk of having adverse drug reactions or therapeutic failure to standard dosages of CYP2C19 substrates.

CYP2C9 – Metabolizes approximately 10% of all drugs, including warfarin, phenytoin, non-steroidal anti-inflammatory drugs (NSAIDs), and antihyperglycemic sulphonylureas.  Detecting variants of the CYP2C9 gene that cause altered enzymatic activity can identify patients who may be at increased risk of having adverse drug reactions or therapeutic failure to standard dosages of CYP2C9 substrates.

CYP3A4 - A liver enzyme that, in concert with CYP3A5, metabolizes approximately 50% of medications, including many of the statins, benzodiazepines, antibiotics, and antipsychotics. Detecting variants of the CYP3A4 gene that cause altered enzymatic activity can identify patients who may be at increased risk of having adverse drug reactions while taking standard dosages of 3A4 substrates. Roughly 4-10% of the general population possesses inherited differences in 3A4 that cause decreased metabolism. These Decreased Metabolizers may be at increased risk for dose-dependent side effects to drugs normally inactivated by 3A4.

 

CYP3A5 – A liver enzyme that, in concert with CYP3A4, metabolizes approximately 50% of medications, including many of the statins, benzodiazepines, antibiotics, and antipsychotics. Detecting variants of the CYP3A5 gene that cause altered enzymatic activity can identify patients who may be at increased risk of having adverse drug reactions while taking standard dosages of 3A5 substrates. More than half of the general population (60-80%) possesses inherited differences in 3A5 that cause decreased metabolism. These Decreased Metabolizers may be at increased risk for dose-dependent side effects to drugs normally inactivated by 3A5.

CYP1A2 – Metabolizes many medications, including theophylline, diazepam, caffeine, and amitriptyline.  CYP1A2 can be induced by several medications, substrates, and constituents of tobacco smoke.  CYP1A2 can also be inhibited by several medications.  Basal metabolic capacity remains relatively consistent among the different genotypes in the absence of an inducer.  Detecting variants of the CYP1A2 gene that cause altered enzymatic induction in the presence of an inducer can identify patients who may be at increased risk of having adverse drug reactions or therapeutic failure to standard dosages of CYP1A2 substrates.

SLC6A4 The 5-HTTLPR (5-hydroxytryptamine transporter linked polymorphic region) polymorphism is a 44-bp insertion/deletion in the promoter region of the serotonin transporter gene, 5-HTT or SLC6A4. The two most frequent alleles are defined by their length: the (L)ong allele, and the (S)hort allele characterized by a 43-bp deletion. The S allele results in 50% less expression of the active transporter protein as compared to the Long form. Presence of the short form may increase the time to therapeutic response with selective serotonin antidepressant therapy and may also affect efficacy. The short form has also been associated increased risk of side effects, and the nature and extent of depressive symptoms experienced. The Long allele of 5-HTTLPR contains an A>G polymorphism which generates a restriction site that may be detected by restriction fragment length polymorphism analysis. Presence of the G allele is thought to result in a phenotype similar to that of the Short 5-HTTLPR allele. Therefore, the presence of the LG allele is associated with the same risks as that of the Short allele.

OPRM1 – Opioid agonists, such as morphine, hydromorphone, and oxymorphone, exert their analgesic properties via stimulation of the mu-1 opioid receptor. Analgesic efficacy of mu-acting drugs has been linked to the 118A>G single nucleotide polymorphism (SNP) of OPRM1, the gene encoding the mu-1 receptor. The frequency of the variant G allele varies from 10% to 48% depending on the population studied. Studies show that patients carrying the GG (homozygous variant) genotype require much higher opioid doses to achieve pain relief.  Additionally, patients with the AA genotype display higher relapse rates with respect to naltrexone treatment for alcohol dependence.

MTHFR – The MTHFR (Methylenetetrahydrofolate Reductase) enzyme catalyzes the formation of 5-methyltetrahydrofolate, the major circulating form of active folate.  Absence of active folate leads to accumulation of plasma homocysteine.  The 677 C>T polymorphism of MTHFR leads to decreased MTHFR enzymatic activity and elevated homocysteine.  The 1298 A>C polymorphism is associated with significant increases plasma homocysteine levels only when in combination with the 677 C>T polymorphism.   Elevated plasma homocysteine has been shown to be a risk factor for atherosclerotic heart disease, myocardial infarction, cerebrovascular disease, and venous thrombosis.  Additionally, associations between the 677 C>T polymorphism and increased risk for methotrexate toxicity, increased chemosensitivity of colon and breast cancers to 5-fluorouracil, and increased risk of fetal neural tube defects in pregnant women have also been reported, although these associations remain controversial.

COMT – This enzyme degrades dopamine and norepinephrine, primarily in the prefrontal cortex of the brain. A common single nucleotide polymorphism (SNP) 472G>A, also referred to by the amino acid change 158 Val>Met, is associated with altered COMT enzymatic activity.  The 158 Met allele has lower enzymatic activity resulting in less dopamine degradation and higher dopamine concentrations as compared to those carrying the Val allele. Conversely, the 158 Val allele has higher activity and results in lower dopamine levels in the prefrontal cortex.  Low dopamine concentrations are associated with cognitive impairments including working memory deficits.  Val/Val homozygotes with depression are less likely to achieve remission when treated with SSRI antidepressants, and Val/Val homozygotes with schizophrenia are less likely to demonstrate improved cognitive effects when treated with antipsychotics.  In contrast, the Met/Met homozygotes are more likely to achieve remission and demonstrate cognitive improvement when treated with SSRIs and antipsychotics, respectively.  The frequency of the 158 Met variant varies from 25-43% depending on the population studied.

References 

1) Menu of Tests [Internet]Louisville, KY: PGXL Laboratories; c2016 [cited 2016 11/20]. Available from: http://www.pgxlab.com/test-menu/.

2) Pathways for common medications. Louisville, KY: PGXL Laboratories; 2016:PGXL Primer. Personalized Medicine. Results For Life.

3) Powell G, Holmes EAF, Plumpton CO, Ring A, Baker GA, Jacoby A, Pirmohamed M, Marson AG, Hughes DA. Pharmacogenetic testing prior to carbamazepine treatment of epilepsy: Patients' and physicians' preferences for testing and service delivery. Br J Clin Pharmacol 2015 11;80(5):1149-59.

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